Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-:1].[Na+].[OH2:3].[NH2:4][C:5]1[N:10]=[CH:9][N:8]=[C:7]2[N:11]([CH:15]([C:17]3[C:18]([O:33][CH3:34])=[C:19]([C:25]4[CH:26]=[N:27][CH:28]=[C:29]([CH:32]=4)[C:30]#N)[C:20]([CH3:24])=[C:21]([Cl:23])[CH:22]=3)[CH3:16])[N:12]=[C:13]([CH3:14])[C:6]=12.[ClH:35]>C(O)C>[ClH:23].[ClH:35].[NH2:4][C:5]1[N:10]=[CH:9][N:8]=[C:7]2[N:11]([CH:15]([C:17]3[C:18]([O:33][CH3:34])=[C:19]([C:25]4[CH:26]=[N:27][CH:28]=[C:29]([CH:32]=4)[C:30]([OH:3])=[O:1])[C:20]([CH3:24])=[C:21]([Cl:23])[CH:22]=3)[CH3:16])[N:12]=[C:13]([CH3:14])[C:6]=12
Reactant: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1-c1cncc(C#N)c1
Reactant: [OH-]
Reactant: O
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1-c1cncc(C(=O)O)c1
Temperature: 95 °C

Procedure:
4.0 M Sodium hydroxide in water (0.3 mL, 1 mmol) was added to a mixture of 5-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}nicotinonitrile (0.090 g, 0.21 mmol) in ethanol (1.0 mL) and the mixture was then heated at 95° C. for 6 h. At this time, conc. HCl was added to adjust PH to ˜3. The solvent was removed and the residue was used in the next step without further purification LCMS calculated for C22H22ClN6O3 (M+H)+: m/z=453.1; Found: 453.2.
Reaction SMILES: [C:1](Cl)(=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[OH:14][C@H:15]1[CH2:20][CH2:19][C@H:18]2[C@H:21]3[C@H:30]([CH2:31][CH2:32][C@:16]12[CH3:17])[C@@H:29]1[C:24](=[CH:25][C:26](=[O:33])[CH2:27][CH2:28]1)[CH2:23][C@H:22]3[CH3:34].OS(O)(=O)=O>>[CH3:34][C@@H:22]1[CH2:23][C:24]2[C@H:29]([CH2:28][CH2:27][C:26](=[O:33])[CH:25]=2)[C@@H:30]2[C@@H:21]1[C@H:18]1[C@@:16]([CH2:32][CH2:31]2)([CH3:17])[C@@H:15]([O:14][C:1](=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:20][CH2:19]1
Reactant: CCCCCCCCCCC(=O)Cl
Reactant: C[C@@H]1CC2=CC(=O)CC[C@@H]2[C@H]2CC[C@]3(C)[C@@H](O)CC[C@H]3[C@@H]21
Agent: O=S(=O)(O)O
Product: CCCCCCCCCCC(=O)O[C@H]1CC[C@H]2[C@H]3[C@H](CC[C@]12C)[C@H]1CCC(=O)C=C1C[C@H]3C
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A total of 2.23 grams of commercially available undecanoyl chloride were added to a stirred solution of 1.58 grams of (7α,17β)-17-hydroxy-7-methylestr-4-en-3-one at 0-5° C. The reaction mixture was allowed to reach room temperature and stirred overnight. Thereafter, ice was added and after stirring for another 2 hours the reaction mixture was poured into ice-water, containing 4 ml of conc. H2SO4, followed by ethyl acetate extraction. The organic layers were washed with water, cold 1 N NaOH solution and brine, dried on sodium sulfate, filtered and evaporated in vacuo. The residue was chromatographed over silica Elution with heptane-ethylacetate (4:1) and evaporation gave a greasy solid that was collected. Yield 1.42 g, [α]D20=+36° (c=1; dioxane), MS (ESI): 456.
Reaction SMILES: [CH:1]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][O:5][C:3](=[O:4])[CH:2]=1.[CH2:11](O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl.C1COCC1.CN(C)C1C=CN=CC=1>[O:4]=[C:3]1[CH:2]=[CH:1][C:7]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])=[CH:6][O:5]1
Reactant: OCc1ccccc1
Reactant: O=C(O)c1ccc(=O)oc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)c1ccc(=O)oc1
Temperature: 23 °C
Reaction time: 0.25 h

Procedure:
A solution of coumalic acid (1.2 g, 8.57 mmol) in DCM (20 mL) and THF (20 mL) was treated with 4-dimethylaminopyridine (0.105 g, 0.857 mmol). The reaction was stirred under nitrogen at 23° C. After 15 min, benzyl alcohol (0.886 mL, 8.57 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.642 g, 8.57 mmol) were added, and the stirring was continued. After 5 h, the solution was diluted with DCM (200 mL) and the mixture was washed with water (150 mL), dried over MgSO4, concentrated in vacuo and purified by silica gel chromatography (eluent: 5-25% EtOAc/hexane), affording the title compound as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 8.32 (s, 1H), 7.80 (dd, J=9.78, 2.15 Hz, 1H), 7.33-7.48 (m, 5H), 6.33 (d, J=9.78 Hz, 1H), 5.31 (s, 2H). MS (ESI, positive ion) m/z: 231.1 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[F:9].C([O-])([O-])=O.[K+].[K+].Br[CH2:17][CH2:18][O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:17][CH2:18][O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])=[CH:4][C:3]=1[F:9]
Reactant: Oc1ccc(Br)c(F)c1
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)(C)[Si](C)(C)OCCOc1ccc(Br)c(F)c1
Yield: 79 %

Procedure:
In a manner similar to the method described in example 132a, 4-bromo-3-fluoro-phenol (12 g, 62.3 mmol) was reacted with K2CO3 (26 g, 188 mmol) and (2-bromo-ethoxy)-tert-butyl-dimethyl-silane (18.0 g, 75.3 mmol) to give [2-(4-bromo-3-fluoro-phenoxy)-ethoxy]-tert-butyl-dimethyl-silane as yellow oil (17.2 g, 77%).
Reaction SMILES: [NH2:1][C@H:2]([C:13]([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[NH:22]([C:58]([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[O:59])[C@H:23]([C:39]([NH:41][C@H:42]([C:55](O)=[O:56])[CH2:43][CH2:44][CH2:45][CH2:46][NH:47][C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])=[O:40])[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:27][CH:26]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl.CN(C=O)C>[NH:22]([C:58]([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[O:59])[C@H:23]([C:39]([NH:41][C@H:42]([C:55]([NH:1][C@H:2]([C:13]([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1)=[O:56])[CH2:43][CH2:44][CH2:45][CH2:46][NH:47][C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])=[O:40])[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:27][CH:26]=1
Reactant: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)Nc1ccccc1
Reactant: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)OC(C)(C)C)C(=O)O
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)OC(C)(C)C)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)Nc1ccccc1
Yield: 63.1 %

Procedure:
compound SP306P. Same procedure as above with Trp-NHPh (99.6 mg, 0.356 mmol), N-Boc-Tyr(Bn)-Lys(Boc)-OH (214 mg, 0.356 mmol), EDC (75.3 mg, 0.392 mmol) and HOBt (53.7 mg, 0.397 mmol) in CH2Cl2/DMF (1.5 mL, 1/1). The crude residue was triturated with MeOH/pentane to afford a white solid (193.5 mg, 63%). 1H NMR (300 MHz, DMSO-d6) δ 1.21-1.62 (m, 6H, 3 CH2 Lys), 1.3 (s, 9H, (CH3)3), 1.36 (s, 9H, (CH3)3), 2.64 (m, 1H, CH2 Tyr), 2.87 (m, 3H, CH2 Lys, CH2 Tyr), 3.05 (dd, J=14.7 Hz, J=7.7 Hz, 1H, CH2 Trp), 3.19 (dd, J=14.7 Hz, J=6.2 Hz, 1H, CH2 Trp), 4.11 (m, 1H, CHα), 4.31 (m, 1H, CHU), 4.71 (m, 1H, CHU), 5.02 (s, 2H, CH2 (Bn)), 6.71 (m, 1H), 6.87-7.42 (m, 17H), 7.58 (m, 3H), 7.9 (d, J=7.3 Hz, 1H), 8.18 (d, J=7.2 Hz, 1H), 10 (s, 1H), 10.8 (s, 1H). 13C NMR (75 MHz, DMSO-d6) δ 22.5, 29.2, 32 (3 CH2 Lys), 27.8 (CH2 Trp), 28.1, 28.2 (2 (CH3)3), 36.3 (CH2 Tyr), 39.8 (CH2 Lys), 52.4, 54.2, 55.8 (CHα Tyr, Lys, Trp), 69.1 (CH2 (Bn)), 77.3, 78.1 (2 C(CH3)3), 109.6, 111.2, 114.3, 118.2, 118.4, 119.4, 120.8, 123.3, 123.4, 127.3, 127.5, 127.7, 128.3, 128.6, 130.1, 130.2, 136, 137.2, 138.8 (25 aromatic C), 155.2, 155.5, 156.8 (Car-O, 2 CO carbamate), 170.1, 171.5, 171.6 (3 CO amide). Anal. Calcd. for C49H60N6O8, 1.5H2O: C, 66.27; H, 7.15; N, 9.46. Found: C, 66.42; H, 6.96; N, 9.34.
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:6](=[CH:7][C:8]3[C:9]4[C:14]=2[C:13](=[O:16])[N:12]([CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])[C:11](=[O:22])[C:10]=4[CH:23]=[CH:24][CH:25]=3)[CH:5]=[CH:4][CH:3]=1.[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]=[C:35]=[S:36])=[CH:30][CH:29]=1>C(#N)C>[CH3:21][N:19]([CH3:20])[CH2:18][CH2:17][N:12]1[C:11](=[O:22])[C:10]2[CH:23]=[CH:24][CH:25]=[C:8]3[C:9]=2[C:14](=[C:15]2[C:2]([NH:1][C:35]([NH:34][C:31]4[CH:32]=[CH:33][C:28]([O:27][CH3:26])=[CH:29][CH:30]=4)=[S:36])=[CH:3][CH:4]=[CH:5][C:6]2=[CH:7]3)[C:13]1=[O:16]
Reactant: CN(C)CCN1C(=O)c2cccc3cc4cccc(N)c4c(c23)C1=O
Reactant: COc1ccc(N=C=S)cc1
Solvent: CC#N
Product: COc1ccc(NC(=S)Nc2cccc3cc4cccc5c4c(c23)C(=O)N(CCN(C)C)C5=O)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
300 mg of 11-amino-2-[2-(dimethylamino)ethyl]-1H-dibenzo[de,h]isoquinoline-1,3(2H)-dione (obtained in example 3) (0.90 mmole) are dissolved in 20 ml of acetonitrile. 250 μl (2 molar equivalents) of 4-methoxyphenyl isothiocyanate was added and the reaction mixture was maintained at room temperature for 16 hours. Two more equivalents of 4-methoxyphenyl isothiocyanate was added and the reaction mixture was stirred for 24 hours at room temperature. The solvent was then evaporated under reduced pressure and the residue was submitted to a flash chromatography (SiO2, CH2Cl2/MeOH 95/5). 409 mg of UN the desired product (formula shown hereinabove) were isolated as a red powder (yield=91%) which was characterized as follows:
Reaction SMILES: [Br:1][CH:2]([CH3:19])[C:3]([C:5]1[CH:6]=[N:7][N:8]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[CH:9]=1)=O.[I:20][C:21]1[N:26]=[C:25]([NH:27][C:28]([NH2:30])=[S:29])[CH:24]=[CH:23][CH:22]=1>CC(C)=O>[BrH:1].[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][N:8]2[CH:9]=[C:5]([C:3]3[N:30]=[C:28]([NH:27][C:25]4[CH:24]=[CH:23][CH:22]=[C:21]([I:20])[N:26]=4)[S:29][C:2]=3[CH3:19])[CH:6]=[N:7]2)=[CH:12][CH:13]=1
Reactant: NC(=S)Nc1cccc(I)n1
Reactant: COc1ccc(Cn2cc(C(=O)C(C)Br)cn2)cc1
Solvent: CC(C)=O
Product: Br
Product: COc1ccc(Cn2cc(-c3nc(Nc4cccc(I)n4)sc3C)cn2)cc1
Yield: 63.9 %

Procedure:
According to Scheme 2 Step 4: A solution of 2-bromo-1-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)propan-1-one (0.36 mmol, 116 mg) and of 1-(6-iodopyridin-2-yl)thiourea (0.36 mmol, 100 mg) in acetone (1.8 mL) was stirred at 60° C. for 2 days. The precipitate formed was filtered and was washed with Et2O to yield N-(4-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-5-methylthiazol-2-yl)-6-iodopyridin-2-amine hydrobromide (0.23 mmol, 136 mg, 65%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[F:9].CC(C)([O-])C.[K+].Cl[C:17]1[CH:22]=[CH:21][N:20]=[C:19]([C:23]([NH:25][CH3:26])=[O:24])[CH:18]=1>CN(C)C(=O)C>[CH3:26][NH:25][C:23]([C:19]1[CH:18]=[C:17]([O:8][C:5]2[CH:6]=[CH:7][C:2]([NH2:1])=[C:3]([F:9])[CH:4]=2)[CH:22]=[CH:21][N:20]=1)=[O:24]
Reactant: CNC(=O)c1cc(Cl)ccn1
Reactant: Nc1ccc(O)cc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CNC(=O)c1cc(Oc2ccc(N)c(F)c2)ccn1

Procedure:
In the first step 4-amino-3-fluorophenol was treated with potassium tert-butoxide and 4-chloro-N-methyl-2-pyridinecarboxamide was added in N,N-dimethylacetamide to form 4-(4-amino-3-fluorophenoxy)pyridine-2-carboxylic acid methylamide which after extraction was finally treated with 4-chloro-3-(trifluoromethyl)phenyl isocyanate in toluene to form 4{4-[3-(4-chloro-3-trifluoromethylphenyl)-ureido]-3-fluorophenoxy}-pyridine-2-carboxylic acid methylamide which is the compound of formula (I).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[C:13](Cl)[N:14]=1)[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].O.[NH2:17][NH2:18]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[C:13]([NH:17][NH2:18])[N:14]=1)[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6]
Reactant: CC(C)(C)OC(=O)c1cc(Cl)nc(Cl)c1
Reactant: NN
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)c1cc(Cl)nc(NN)c1
Temperature: 75 °C
Reaction time: 18 h

Procedure:
To a solution of tert-butyl 2,6-dichloroisonicotinate (11.0 g, 44.3 mmol) in ethanol (222 mL) was added hydrazine hydrate (6.46 mL, 133 mmol). The mixture was heated 75° C. After 18 h, the mixture was cooled to ambient temperature. The mixture was concentrate down to half of the volume. The solid crashed out was filtered off and the filtrate was concentrated to dryness: LC-MS [M+1]=244.1.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([O:14][C:15]2[C:16]3[C:23]([C:24]4[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=4)=[C:22]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=4[F:38])[O:21][C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:9]1)C1C=CC=CC=1.[CH:39]([OH:41])=[O:40]>CO.[Pd]>[CH:39]([OH:41])=[O:40].[F:38][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=1[C:22]1[O:21][C:17]2[N:18]=[CH:19][N:20]=[C:15]([O:14][C@@H:10]3[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]3)[C:16]=2[C:23]=1[C:24]1[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=1
Reactant: COc1ccc(-c2c(-c3ccccc3F)oc3ncnc(O[C@@H]4CCCN(Cc5ccccc5)C4)c23)cc1
Agent: [Pd]
Solvent: CO
Solvent: O=CO
Product: COc1ccc(-c2c(-c3ccccc3F)oc3ncnc(O[C@@H]4CCCNC4)c23)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Add 400 mg of palladium black to an argon-blanketed solution of 510 mg (1.00 mmol) of 4-{[(3R)-1-benzylpiperidin-3-yl]oxy}-6-(2-fluorophenyl)-5-(4-methoxyphenyl)furo[2,3-d]pyrimidine in 5 ml of a 4.4% solution of formic acid in methanol, and stir at room temperature for two days. After filtering off the catalyst, wash the catalyst residue with methanol/water. Concentrate the filtrate under reduced pressure and purify the residue by means of preparative RP-HPLC (eluent: water/acetonitrile gradient with 0.1% formic acid). 70 mg (12% of theory, 80% purity) of the desired product are obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][OH:16])=[CH:11][CH:10]=2)[O:3]1.N1C=CC=CC=1.ClC(OC1C=[CH:32][C:31]([N+:34]([O-])=O)=[CH:30]C=1)=O.C1C[O:40][CH2:39]C1>>[CH3:8][C:6]1([CH3:7])[C:2]([CH3:17])([CH3:1])[O:3][B:4]([C:9]2[CH:10]=[CH:11][C:12]([CH2:15][O:16][C:39](=[O:40])[NH:34][CH:31]([CH3:30])[CH3:32])=[CH:13][CH:14]=2)[O:5]1
Reactant: C1CCOC1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC1(C)OB(c2ccc(CO)cc2)OC1(C)C
Solvent: c1ccncc1
Product: CC(C)NC(=O)OCc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of [4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-methanol (2.34 g, 10 mmol) and pyridine (890 ul, 11 mmol) in THF (50 ml) at rt was added dropwise a solution of 4-nitrophenyl chloroformate (2.22 g, 11 mmol) in THF (10 ml). The reaction mixture was stirred at rt for overnight. The precipitate was removed by filtration. The filtrate was concentrated to give the desired compound (4.2 g, may contain some pyridine HCl salt).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][NH:11][C:12]3=[O:17])=[CH:4][CH:3]=1.[OH-].[Na+].[C:20](Cl)(OCC(Cl)(Cl)Cl)=[O:21].[NH2:29][C:30]1[NH:34][N:33]=[C:32]([C:35]([CH3:38])([CH3:37])[CH3:36])[CH:31]=1.CCN(C(C)C)C(C)C>CCOC(C)=O.O>[C:35]([C:32]1[CH:31]=[C:30]([NH:29][C:20]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[CH:16]=[CH:15][CH:14]=[C:13]4[C:9]=3[CH2:10][NH:11][C:12]4=[O:17])=[CH:6][CH:7]=2)=[O:21])[NH:34][N:33]=1)([CH3:38])([CH3:37])[CH3:36]
Reactant: Nc1ccc(-c2cccc3c2CNC3=O)cc1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: CC(C)(C)c1cc(N)[nH]n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)(C)c1cc(NC(=O)Nc2ccc(-c3cccc4c3CNC4=O)cc2)[nH]n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 47.5 %

Procedure:
To a solution of 4-(4-aminophenyl)isoindolin-1-one (0.327 g, 1.46 mmol, made according to literature procedures) in EtOAc (5 mL) was added NaOH (2N, 2 mL, 4 mmol) and Troc-Cl (0.618 g, 2.92 mmol) and the resulting mixture was stirred at RT for 6 h. Water (20 mL) was added and the mixture was extracted with EtOAc (3×20 mL), dried (MgSO4) and concentrated. The residue was dissolved in DMF (2 mL) to which was added 5-amino-3-t-butylpyrazole (0.831 g, 5.97 mmol, made according to literature procedures) and i-Pr2NEt (0.406 g, 2.92 mmol) and the solution was stirred at 90° C. overnight. Water (100 mL) was added and the mixture was extracted with EtOAc (3×100 mL), dried (MgSO4) and concentrated. Addition of CH2Cl2 to the residue resulted in precipitation of the product. The product was collected and dried to yield 1-(3-t-butyl-1H-pyrazol-5-yl)-3-(4-(1-oxoisoindolin-4-yl)phenyl)urea (270 mg, 48% yield) as a light brown powder. 1H-NMR (DMSO-d6): δ 9.31 (s, br, 1H), 8.95 (s, br, 1H), 8.65 (s, br, 1H), 7.65-7.63 (m, 2H), 7.58-7.52 (m, 5H), 6.00 (s, br, 1H), 4.51 (s, 2H), 1.25 (s, 9H), one NH is not visible. MS expected 390.2 found 390.2.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.C1(N=C=NC2CCCCC2)CCCCC1.[NH2:26][CH2:27][CH2:28][CH2:29][NH:30][CH2:31][CH2:32][CH2:33][CH2:34][NH:35][CH2:36][CH2:37][CH2:38][NH2:39]>ClCCl>[OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH:39][CH2:38][CH2:37][CH2:36][NH:35][CH2:34][CH2:33][CH2:32][CH2:31][NH:30][CH2:29][CH2:28][CH2:27][NH2:26])=[O:7]
Reactant: NCCCNCCCCNCCCN
Reactant: O=C(O)c1cccc(O)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: NCCCNCCCCNCCCNC(=O)c1cccc(O)c1
Reaction time: 17 h

Procedure:
According to the General Procedure using 3-Hydroxybenzoic acid (138 mg, 1.00 mMol), dicyclohexylcarbodiimide (226 mg, 1.10 mMol), and spermine (400 mg, 1.98 mMol) in dichloromethane (6 ml), activation during 3 h and coupling over 17 h. The product was eluted over silica gel with dichloromethane/methanol/0.880 ammonia solution (4:2:1). The desired amide was in fractions 8-13 was homogeneous when monitored by tlc on silica (CH2Cl2 /MeOH/NH4OH, 4:2:1), Rf =0.29, (76 mg, 24%), lyophilisation gave 52 mg of a colorless, viscous oil whose spectroscopic data include:pmr (90 MHz, 2H2O) 1.4-1.9 (m, 8H, 4×CH2 --CH2), 2.5-2.9 (m, 10H, 5×CH2 --N), 3.25 (t, J=7, 2H, CON2H--CH2 --CH2), 6.5-6.8 (m, 3H, 3× ArH 2,4,6), and 7.0-7.3 (m, 1H, ArH 5) ppm; M+1 323 (FAB matrix m-nitrobenzyl alcohol and sodium chloride) C17H30N4O2 requires M+ 322).
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[C:4]([F:20])[C:5]([CH3:19])=[C:6]2[C:11]=1[N:10]([CH:12]1[CH2:14][CH2:13]1)[CH:9]=[C:8]([C:15]([OH:17])=[O:16])[C:7]2=[O:18].[NH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>C(#N)C>[Cl:1][C:2]1[C:3]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[C:4]([F:20])[C:5]([CH3:19])=[C:6]2[C:11]=1[N:10]([CH:12]1[CH2:14][CH2:13]1)[CH:9]=[C:8]([C:15]([OH:17])=[O:16])[C:7]2=[O:18]
Reactant: Cc1c(F)c(F)c(Cl)c2c1c(=O)c(C(=O)O)cn2C1CC1
Reactant: C1CNCCN1
Solvent: CC#N
Product: Cc1c(F)c(N2CCNCC2)c(Cl)c2c1c(=O)c(C(=O)O)cn2C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.6 %

Procedure:
A suspension of 0.38 g (1.21 mmol) of 8-chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid, 0.42 g (4.88 mmol) of piperazine and 20 ml of acetonitrile was refluxed for four hours, then stirred at room temperature overnight. The precipitate was filtered and washed with water and acetonitrile to give 0.32 g of the title compound, mp 234°-235° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([NH2:13])[CH3:12])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(=O)([O-])[O-].[Na+].[Na+].C(N1[C:29](=[O:30])[C:28]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:27]2[C:26]1=[O:35])(OCC)=O>O.C(#N)C>[C:26]1(=[O:35])[N:13]([CH:11]([C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)[CH3:12])[C:29](=[O:30])[C:28]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:27]12
Reactant: COc1ccc(C(C)N)cc1OC
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: COc1ccc(C(C)N2C(=O)c3ccccc3C2=O)cc1OC
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 27.3 %

Procedure:
1-Phthalimido-1-(31, 4′-dimethoxyphenyl)ethane. To a stirred solution of 1-(3′,4′-dimethoxyphenyl)ethylamine (1.81 grams, 10.0 mmol) and sodium carbonate (1.14 grams, 10.8 mmol) in a mixture of water (80 miilliters) and acetonitrile (50 milliliters) was add N-carbethoxyphthalimide (2.19 grams, 10 mmol). The resulting suspension was stirred for 3.5 hours at room temperature and the filtered to afford 1.24 grams (40%) of the crude product as a white powder. The crude product was recrystallized from hexane/ethyl acetate and dried in vacuo (60° C., <1 mm) to afford 0.85 grams (27%) of the product as white crystals: mp 124-125° C.; 1H NMR (CDCl3) δ 7.96-7.78 (m, 4H), 7.09-6.81 (m, 3H), 5.40 (q, J=7.2 Hz, 1H), 3.73 (s, 3H), 3.72 (s, 3H), 1.81 (d, J=7.2 Hz, 3H); 13C NMR (DMSO-d6) δ 167.6, 148.4, 148.0, 134.4, 132.9, 131.3, 122.9, 118.8, 111.5, 110.8, 55.4, 48.6, 17.7. Anal. Calculated for C18H17NO4. Theoretical: C, 69.44; H, 5.50; N, 4.50. Found: C, 69.63; H, 5.45; N, 4.42. HPLC 100%.
Reaction SMILES: [C:1]([C:3]1[N:8]=[C:7]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])=[O:16])[CH:6]=[CH:5][CH:4]=1)#[N:2].[C:24](OC)(=[O:32])[C:25]1[C:26](=[CH:28][CH:29]=[CH:30][CH:31]=1)[SH:27].C(N(CC)CC)C>C1(C)C=CC=CC=1>[O:32]=[C:24]1[C:25]2[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=2[S:27][C:1]([C:3]2[N:8]=[C:7]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH2:19][Si:20]([CH3:22])([CH3:23])[CH3:21])=[O:16])[CH:6]=[CH:5][CH:4]=2)=[N:2]1
Reactant: COC(=O)c1ccccc1S
Reactant: C[Si](C)(C)CCOC(=O)CCCCCCc1cccc(C#N)n1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: C[Si](C)(C)CCOC(=O)CCCCCCc1cccc(-c2nc(=O)c3ccccc3s2)n1
Yield: 50.7 %

Procedure:
2-(Trimethylsilyl)ethyl 7-(6-cyano-2-pyridyl)heptanoate (0.52 g, 1.6 mmol) and methyl thiosalicylate (0.43 g, 2.5 mmol) were dissolved in toluene (2 ml), and triethylamine (0.44 ml, 2.3 mmol) was added thereto. The reaction mixture was refluxed for 16 hrs and subjected to a silica gel (35 g) column chromatography. The fractions eluted with hexane-ethyl acetate (4:1, v/v) were collected and concentrated to give the titled compound (0.38 g, 27%) as a yellow oil.
Reaction SMILES: [CH:1]([N:4]1[C:9](=[O:10])[CH:8]2[CH2:11][C:6]([C:12]3[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=3)([CH2:7]2)[C:5]1=[O:21])([CH3:3])[CH3:2].C(OCC)(=O)C.CCCCCC>C(OCC)(=O)C.[Pd]>[NH2:18][C:15]1[CH:14]=[CH:13][C:12]([C:6]23[CH2:7][CH:8]([CH2:11]2)[C:9](=[O:10])[N:4]([CH:1]([CH3:2])[CH3:3])[C:5]3=[O:21])=[CH:17][CH:16]=1
Reactant: CC(C)N1C(=O)C2CC(c3ccc([N+](=O)[O-])cc3)(C2)C1=O
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(C)N1C(=O)C2CC(c3ccc(N)cc3)(C2)C1=O

Procedure:
In a manner analogous to that described in Example 1a, 2.3 g of 3-isopropyl-1-(4-nitrophenyl)-3-azabicyclo[-3.1.1]-heptane-2,4-dione are dissolved in 50 ml of ethyl acetate, hydrogenated in the presence of 0.25 g of 5% palladium-on-carbon and worked up. Melting point 191°-201° (from ethyl acetate/hexane).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][CH:11]([CH3:13])[CH3:12])[CH:9]=1)[C:5]#N.[OH2:14].[OH-:15].[Na+]>CCO>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][CH:11]([CH3:13])[CH3:12])[CH:9]=1)[C:5]([OH:15])=[O:14]
Reactant: [OH-]
Reactant: O
Reactant: CC(C)Oc1cc(Br)cc(C#N)c1
Agent: [Na+]
Solvent: CCO
Product: CC(C)Oc1cc(Br)cc(C(=O)O)c1
Yield: 100 %

Procedure:
To a solution of 3-bromo-5-isopropoxy-benzonitrile (6.0 g, 24.78 mmol) in EtOH (80 ml) was added water (8.0 ml), followed by 50% NaOH (6.52 ml, 123.91 mmol). The reaction mixture was then refluxed for 2 hrs, concentrated down, re-dissolved in water, acidified with HCl, extracted with EtOAc. The EtOAc layer was separated, dried over MgSO4, filtrated, and concentrated to afford the final product 3-bromo-5-isopropoxy-benzoic acid (6.36 g, 100%). 1H NMR (300 MHz, DMSO-d6): δ 13.31 (s, 1H), 7.56 (s, 1H), 7.36 (m, 2H), 4.70 (m, 2H), 1.25 (d, J=6.0 Hz, 6H). LC-MS m/z=260.4 [C10H11BrO3+H]+.